Prostate cancer (PCa) will kill an estimated 33,720 men in the US alone this year. The integral membrane protein prostate-specific membrane antigen (PSMA) is becoming increasingly recognized as a viable target for imaging and therapy of prostate and other forms of cancer. PSMA is significantly over-expressed in PCa and metastases, particularly with respect to the castration-resistant form. Accordingly, PSMA may provide a negative prognostic indicator for PCa—enabling distinction of indolent from aggressive disease. Imaging PSMA has also provided insight into androgen signaling and information on response to taxane therapy.
Recently the present inventors and others have demonstrated successful PSMA-targeted radionuclide imaging in experimental models of PCa using cysteine-glutamate or lysine-glutamate ureas. With those agents the radionuclide (11C, 125I, 18F) is attached to the cysteine or lysine moiety via a small prosthetic group. For large molecular fragments, such as radiometal (99mTc, 68Ga, 111In) chelators, organic fluorescent molecules, and nanoparticles, we have determined that a linking moiety of at least 20 Å (long-linker) between the large molecule and the lysine moiety facilitates productive binding. We have also developed a PSMA-targeted, dual (radionuclide and optical) modality imaging platform that enables sequential, dual modality imaging.
Various approaches have been reported to exploit multivalent scaffolds for the construction of molecular imaging probes. However, the chemistry used to produce them can become complicated, even more so when a bifunctional chelator must be attached to a separately multimerized construct to introduce a radionuclide, for example, for imaging. Although, the concept of multimerization for PSMA targeted, near-infrared imaging agents has been proffered for in vitro cell binding studies, to our knowledge a multivalent PSMA-binding agent has not yet been shown to image PSMA successfully in vivo.
Therefore, there still exists a need to provide better and more convenient methods for creating scaffolds for multimeric presentation of PSMA and other targeting species including bivalent and multivalent forms, over the corresponding monomer, to target antigens in vivo.